Date: 2017-04-03
Type of
information: Results
phase: 1-2
Announcement: results
Company: XBiotech (USA - TX)
Product: 514G3
Action
mechanism: monoclonal antibody. 514G3 was developed from a healthy human donor with natural antibodies effective at neutralizing MRSA and non-MRSA forms of S. aureus. 514G3 knocks out the principle immune evasion mechanism of the bacteria, allowing white blood cells to detect and destroy the bacteria. 514G3 has potential to treat all strains of MRSA and can be used without consideration for strain-specific resistance to various antibiotics. As a True Human monoclonal antibody, 514G3 is expected to be well tolerated without the side effects or risks of antibiotics, including the lack of risk of antibiotic resistance.
Disease: Staphylococcus Aureus bacteremia
Therapeutic
area: Infectious diseases
Country: USA
Trial
details: This study will evaluate the maximum safe dose of the true human monoclonal antibody, 514G3, in the treatment of patients with Staphylococcus Aureus bacteremia. Preliminary evidence of efficacy will be evaluated as well. Patients will receive 514G3 plus antibiotics or placebo plus antibiotics in approximately a 3 to 1 ratio.(NCT02357966)
Latest
news:
- • On April 3, 2017, XBiotech announced top-line result from its double-blind, placebo-controlled, phase I-II study evaluating the safety and efficacy of its FDA Fast Tracked true human antibody (514G3) for the treatment of Staphylococcus aureus bloodstream infections. The study involved use of the Company’s proprietary 514G3 antibody derived from a natural human immune response against a key virulence determinant of S. aureus that is present on all strains of the bacteria, including MRSA. In the study, hospitalized adult patients with confirmed blood infections were randomized 3:1 (514G3 vs placebo) during a dose escalation phase to establish a Phase II dose. The Phase II portion was randomized 2:1 at the established Phase II dose of 40 mg/kg. A total of 52 patients were enrolled: 36 received 514G3 and 16 received placebo. Thirty of the 36 patients that were given 514G3 received the established Phase II dose (40 mg/kg).
- The study was the first in-human use for 514G3 using exploratory endpoints in a small population. Thus, the study was not powered to demonstrate statistically significant outcomes. Nevertheless, several key topline results from the clinical study were observed.
- No drug-related adverse events were observed at any of the dose escalation levels and the 40 mg/kg Phase II dose was established without any dose-limiting toxicities (DLTs). The duration of hospitalization and incidence of serious adverse events (SAEs) were key clinical endpoints which the Company is exploring as a basis for evaluating effectiveness of the therapy. SAEs thus served as both a measure of safety and of efficacy for the 514G3 therapy. Blinded analyses for SAEs were independently performed by the study chair, treating investigators, and an independent expert. A total of 28 SAEs in 15 patients were reported during the study period including 4 deaths. There was a 49% relative risk reduction for the overall incidence of SAEs in subjects receiving 514G3 compared to those receiving placebo [(8 of 36 (22%) vs 7 of 16 (44%), respectively, (p=0.11)]. There was an even greater risk reduction in the incidence of S. aureus related SAEs in those that received 514G3 treatment compared to placebo, with a 56% relative risk reduction in the 514G3 group [4 of 36 (11%) vs 4 of 16 (25%), respectively, (p=0.23)]. The trend seen with overall and disease specific reduction in SAEs was a key outcome in the study and an important potential indication of 514G3 efficacy.Another clinically important secondary endpoint was the average length of hospitalization for patients from the time they entered study. The duration of hospitalization was reduced by about 33% in the 514G3 treatment arm compared to the placebo arm [8.6±7 days vs 12.7±9 days, respectively (p=0.092)] [median 7.5 (IQR 4–9) vs median 12 (IQR 5.5–19), respectively]. Given the complexity of the co-morbidities in the population and the small study size, observing reduced hospital stay in the 514G3 group suggests a considerable impact on resolution of disease, less patient morbidity and a potential reduction in healthcare expenditures for subjects receiving the antibody therapy.
- Other findings in this study were that randomization failed in the small sample size to provide well matched populations with respect to co-morbidities between treatment and placebo arms. Subjects who were randomized in the 514G3 treatment arm tended to be sicker and have greater numbers of serious co-morbid conditions and greater risk of complications. Seventy-eight percent of the 514G3 treated patients were admitted to the hospital via the Emergency Department vs 56% in the placebo arm. In addition, observed differences in the primary diagnosis for patients randomized to the 514G3 vs placebo arm included 4 (11%) vs 0 for stroke and 4 (11%) vs 0 for sepsis, respectively. Conversely, for 9 (56%) of the placebo arm patients vs only 11 (31%) of 514G3 patients, staphylococcus infection was associated with underlying cellulitis, which is generally a more mild form of the disease. Consequently, four deaths occurred in the treatment arm vs none in the placebo group (p=0.30). The panel of experts certified in blinded reviews that three of the deaths were unrelated to study drug. For one death, there was uncertainty. Two of the three panel experts deemed that an event for a patient admitted with an acute stroke that died one day following receiving 514G3 treatment was “possibly” related to the test article. Autopsy findings, however, revealed extensive atherosclerosis in the brain and concluded that death was sequelae of a second stroke. Dr. Rupp further related, “Although the deaths observed in the treatment arm of the study did not appear to be drug-related, this will warrant careful evaluation in larger studies. Overall, 514G3 shows promise as an innovative adjunctive approach in the treatment of serious infections due to S. aureus.”
- • On December 6, 2016, XBiotech announced that enrollment has been completed in its randomized, placebo-controlled Phase I/II study evaluating dosing, safety and efficacy of the Company’s novel antibody therapy, 514G3. This proprietary antibody therapy has received Fast Track Designation by the FDA for the treatment of all forms of Staphylococcus aureus infections, including Methicillin-resistant S. aureus (MRSA). The Company reports that top-line findings from the 514G3 study should be reported in first quarter 2017.
- Patients enrolled in the Phase II portion of the study were randomized to receive the highest dose of 514G3, as determined by the Phase I portion of the study, plus standard of care antibiotics vs. placebo plus antibiotics. Patients were treated in hospital settings at sites in the United States, Germany, Taiwan and Korea. In addition to safety and tolerability evaluation, the study includes efficacy measures such as time to clearance of bacteremia (as measured by blood culture), duration of fever, serious adverse events, length of hospitalization and survival. The randomized, blinded Phase II portion has enrolled 36 patients, with 24 of those patients randomized to receive 514G3.
Is
general: Yes
